tbuckley/cabot-search huggingface dataset:
Germ line<i>DDX41</i>mutations define a unique subtype of myeloid neoplasms
Authors: Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steve Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro M. Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Müller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H. Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Satoru Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G. Kulasekararaj, Lucy A. Godley, Jaroslaw P. Maciejewski, Seishi Ogawa
Journal: Blood (2022)

Abstract Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
Optimal Timing of Hemodialysis Before Surgery
Authors: Anthony J. Bleyer
Journal: JAMA (2022)

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Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer
Authors: Mary L. (Nora) Disis, Katherine A. Guthrie, Ying Liu, Andrew L. Coveler, Doreen M. Higgins, Jennifer S. Childs, Yushe Dang, Lupe G. Salazar
Journal: JAMA Oncology (2022)

High levels of ERBB2 (formerly HER2)-specific type 1 T cells in the peripheral blood are associated with favorable clinical outcomes after trastuzumab therapy; however, only a minority of patients develop measurable ERBB2 immunity after treatment. Vaccines designed to increase ERBB2-specific T-helper cells could induce ERBB2 immunity in a majority of patients.
Race and Ancestry in Immune Response to Breast Cancer
Authors: Alina M. Hamilton, Katherine A. Hoadley, Melissa A. Troester
Journal: Cancer Discovery (2022)

Summary: Martini and colleagues performed genetic ancestry estimation on a unique international triple-negative breast cancer (TNBC) study enriched for participants with African ancestry. They identified gene signatures indicative of ancestry in race-associated TNBC and found ancestry-associated immunologic differences that may contribute to racial disparities in breast cancer. See related article by Martini et al., p. 2530 (5).
FcRn‐targeting and ROS‐responsive Fedratinib‐incorporated nanoparticles alleviate asthma by inducing eosinophil apoptosis
Authors: Weimin Sun, Shijie Song, Guangmeng Li, Linghui Zhou, Junmou Xie, Yuhe Guo, Jun Zeng, Junyan Zhang, Linmei Li, Ying He, Jie Yan, Xintao Shuai, Ailin Tao
Journal: Allergy (2022)

Online supporting information Figures S1-S5 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities
Authors: Lorenzo Falchi, Santosha A. Vardhana, Gilles A. Salles
Journal: Blood (2022)

Treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHL) have shifted dramatically in the last 2 decades following the introduction of highly active immunotherapies such as rituximab. Since then, the field has continued to witness tremendous progress with the introduction of newer, more potent immunotherapeutics, including chimeric antigen receptor T-cell therapy, which have received regulatory approval for and currently play a significant role in the treatment of these diseases. Bispecific antibodies (BsAb) are a novel class of off-the-shelf T-cell redirecting drugs and are among the most promising immunotherapeutics for lymphoma today. BsAb may target various cell-surface antigens and exist in different formats. Anti-CD20xCD3 BsAb have demonstrated remarkable single-agent activity in patients with heavily pretreated B-NHL with a manageable toxicity profile dominated by T-cell overactivation syndromes. Much work remains to be done to define the optimal setting in which to deploy these drugs for B-NHL treatment, their ideal combination partners, strategies to minimize toxicity, and, perhaps most importantly, pharmacodynamic biomarkers of response and resistance. In this review, we provide an update on BsAb development in B-NHL, from discovery to clinical applications, highlighting the achievements, limitations, and future directions of the field.
Update in Adult Transgender Medicine
Authors: Alyxandra Ramsay, Joshua D. Safer
Journal: Annual Review of Medicine (2022)

Transgender people often face barriers in health care due to lack of access to care, lack of knowledgeable healthcare professionals, discrimination, and gaps in medical and mental health research. Existing research on transgender health has focused heavily on mental health, HIV/AIDS, sexually transmitted diseases/infections, and substance abuse. Gender-affirming hormone therapy and/or surgery allows for some alignment of biology and gender identity. Gender-affirming care may offer quality-of-life benefits, which may outweigh modest concerns related to exogenous hormone therapy. The Endocrine Society treatment guidelines were revised in 2017, and this article reviews recent data that might inform a future guideline revision. Future longitudinal research is needed to close the gap in knowledge in the field of transgender medicine.
Single-cell methods in myeloproliferative neoplasms: old questions, new technologies
Authors: Jennifer Mary O’Sullivan, Adam J. Mead, Bethan Psaila
Journal: Blood (2022)

Myeloproliferative neoplasms (MPN) are a group of clonal stem cell-derived hematopoietic malignancies driven by aberrant Janus kinase-signal transducer and activator of transcription proteins (JAK/STAT) signaling. Although these are genetically simple diseases, MPNs are phenotypically heterogeneous, reflecting underlying intratumoral heterogeneity driven by the interplay of genetic and nongenetic factors. Their evolution is determined by factors that enable certain cellular subsets to outcompete others. Therefore, techniques that resolve cellular heterogeneity at the single-cell level are ideally placed to provide new insights into MPN biology. With these insights comes the potential to uncover new approaches to predict the clinical course and treat these cancers, ultimately improving outcomes for patients. MPNs present a particularly tractable model of cancer evolution, because most patients present in an early disease phase and only a small proportion progress to aggressive disease. Therefore, it is not surprising that many groundbreaking technological advances in single-cell omics have been pioneered by their application in MPNs. In this review article, we explore how single-cell approaches have provided transformative insights into MPN disease biology, which are broadly applicable across human cancers, and discuss how these studies might be swiftly translated into clinical pathways and may eventually underpin precision medicine.
Metabolism and Colorectal Cancer
Authors: Joseph C. Sedlak, Ömer H. Yilmaz, Jatin Roper
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment.
Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening
Authors: Emily K. Sims, David Cuthbertson, Jamie L. Felton, Heba M. Ismail, Brandon M. Nathan, Laura M. Jacobsen, Emily Paprocki, Alberto Pugliese, Jerry Palmer, Mark Atkinson, Carmella Evans-Molina, Jay S. Skyler, Maria J. Redondo, Kevan C. Herold, Jay M. Sosenko
Journal: Diabetes Care (2022)

We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.
Covid-19 Vaccine Protection among Children and Adolescents in Qatar
Authors: Hiam Chemaitelly, Sawsan AlMukdad, Houssein H. Ayoub, Heba N. Altarawneh, Peter Coyle, Patrick Tang, Hadi M. Yassine, Hebah A. Al-Khatib, Maria K. Smatti, Mohammad R. Hasan, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar H. Kaleeckal, Ali N. Latif, Riyazuddin M. Shaik, Hanan F. Abdul-Rahim, Gheyath K. Nasrallah, Mohamed G. Al-Kuwari, Hamad E. Al-Romaihi, Adeel A. Butt, Mohamed H. Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Laith J. Abu-Raddad
Journal: New England Journal of Medicine (2022)

The BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) has been authorized for use in children 5 to 11 years of age and adolescents 12 to 17 years of age but in different antigen doses.We assessed the real-world effectiveness of the BNT162b2 vaccine against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children and adolescents in Qatar. To compare the incidence of SARS-CoV-2 infection in the national cohort of vaccinated participants with the incidence in the national cohort of unvaccinated participants, we conducted three matched, retrospective, target-trial, cohort studies - one assessing data obtained from children 5 to 11 years of age after the B.1.1.529 (omicron) variant became prevalent and two assessing data from adolescents 12 to 17 years of age before the emergence of the omicron variant (pre-omicron study) and after the omicron variant became prevalent. Associations were estimated with the use of Cox proportional-hazards regression models.Among children, the overall effectiveness of the 10-μg primary vaccine series against infection with the omicron variant was 25.7% (95% confidence interval [CI], 10.0 to 38.6). Effectiveness was highest (49.6%; 95% CI, 28.5 to 64.5) right after receipt of the second dose but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI, 21.5 to 63.3) among children 5 to 7 years of age and 16.6% (95% CI, -4.2 to 33.2) among those 8 to 11 years of age. Among adolescents, the overall effectiveness of the 30-μg primary vaccine series against infection with the omicron variant was 30.6% (95% CI, 26.9 to 34.1), but many adolescents had been vaccinated months earlier. Effectiveness waned over time since receipt of the second dose. Effectiveness was 35.6% (95% CI, 31.2 to 39.6) among adolescents 12 to 14 years of age and 20.9% (95% CI, 13.8 to 27.4) among those 15 to 17 years of age. In the pre-omicron study, the overall effectiveness of the 30-μg primary vaccine series against SARS-CoV-2 infection among adolescents was 87.6% (95% CI, 84.0 to 90.4) and waned relatively slowly after receipt of the second dose.Vaccination in children was associated with modest, rapidly waning protection against omicron infection. Vaccination in adolescents was associated with stronger, more durable protection, perhaps because of the larger antigen dose. (Funded by Weill Cornell Medicine-Qatar and others.).
Association of Hormone Receptors With Clinical Outcomes in Patients With ERBB2-Low Breast Cancer—Reply
Authors: Paolo Tarantino, Nabihah Tayob, Sara M. Tolaney
Journal: JAMA Oncology (2022)

In Reply We appreciate the comments from Cappelletti and colleagues regarding our cohort study on the prognostic and biologic role of ERBB2-low expression in breast cancer.1 The authors raise some valuable points of discussion regarding our work.
Cardiovascular Outcomes in Patients With Both Diabetes and Phenotypic Familial Hypercholesterolemia: A Nationwide Register-Based Cohort Study
Authors: Jonas Brinck, Emil Hagström, Jonatan Nåtman, Stefan Franzén, Katarina Eeg-Olofsson, David Nathanson, Björn Eliasson
Journal: Diabetes Care (2022)

OBJECTIVE Patients with diabetes or familial hypercholesterolemia (FH) have an increased incidence of cardiovascular diseases compared with the population, but whether this risk is exacerbated in patients with combined traits is unknown. RESEARCH DESIGN AND METHODS In this Swedish nationwide, register-based cohort study, patients with diabetes were included between 2002 and 2020. Adjusted Cox proportional hazards models were used to assess the risk of cardiovascular events in patients with or without phenotypic FH (≥6 points for phenotypic FH according to Dutch Lipid Clinic Network criteria) compared with general population control subjects without diabetes as reference. RESULTS A total of 45,585 patients with type 1 diabetes (227,923 control subjects) and 655,250 patients with type 2 diabetes (655,250 control subjects) were followed for a median of 14.1 and 7.9 years, respectively. Of those, 153 and 7,197, respectively, had phenotypic FH. Compared with control subjects, patients with diabetes and phenotypic FH had higher risk of cardiovascular mortality (type 1: hazard ratio 21.3 [95% CI 14.6–31.0]; type 2: 2.40 [2.19–2.63]) and of a cardiovascular event (type 1: 15.1 [11.1–20.5]; type 2: 2.73 [2.58–2.89]). Further, patients with diabetes and phenotypic FH had higher LDL-cholesterol levels during observation (P &amp;lt; 0.05) and increased risk of all major cardiovascular outcomes (P &amp;lt; 0.0001) than patients with diabetes but without FH. The proportion receiving lipid-lowering treatment was higher in patients with phenotypic FH (P &amp;lt; 0.0001). CONCLUSIONS Patients with both diabetes and phenotypic FH are more at risk for adverse cardiovascular outcomes and have higher LDL-cholesterol levels despite receiving intensified lipid-lowering therapy.
Lipid Nanoparticle Delivery of Chemically Modified NGF<sup>R100W</sup> mRNA Alleviates Peripheral Neuropathy
Authors: Xiang Yu, Zheng Yang, Yu Zhang, Jia Xia, Jiahui Zhang, Qi Han, Hang Yu, Chengbiao Wu, Yingjie Xu, Wei Xu, Wen Yang
Journal: Advanced Healthcare Materials (2022)

Messenger RNA (mRNA) carries genetic instructions to the cell machinery for the transient production of antigens or therapeutic proteins and shows enormous potential in vaccine development, cancer immunotherapy, protein replacement therapy, and genome engineering. Here, the synthesis of chemically modified nerve growth factor mutant (NGFR100W ) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon-optimized NGFR100W mRNA yielded high secretion of mature NGFR100W , which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)-delivery of N1-methylpseudouridine-modified mRNA in mice, NGFR100W -mRNA-LNPs result in the successful expression of NGFR100W protein, which significantly reduces nociceptive activity compared to that of NGFWT . This indicates that NGFR100W derived from exogenous mRNA elicited "painless" neuroprotective activity. Additionally, the therapeutic value of NGFR100W mRNA is established in a paclitaxel-induced peripheral neuropathy model by demonstrating the rapid recovery of intraepidermal nerve fibers. The results show that in vitro-transcribed mRNA has significant flexibility in sequence design and fast in vivo functional validation of target proteins. Furthermore, the results highlight the therapeutic potential of mRNA as a supplement to beneficial proteins for preventing or reversing some chronic medical conditions, such as peripheral neuropathy.
Tumor-induced Osteomalacia: A Comprehensive Review
Authors: Salvatore Minisola, Seiji Fukumoto, Weibo Xia, Alessandro Corsi, Luciano Colangelo, Alfredo Scillitani, Jessica Pepe, Cristiana Cipriani, Rajesh V Thakker
Journal: Endocrine Reviews (2022)

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision.
A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis
Authors: Lingjuan Jiang, Mengmeng Shang, Shengnan Yu, Yudong Liu, Hui Zhang, Yangzhong Zhou, Min Wang, Tingting Wang, Hui Li, Zhihua Liu, Xuan Zhang
Journal: Cellular and Molecular Immunology (2022)